Allergic conjunctivitis, ocular inflammation, dermatitis, rhinitis, asthma, allergy, and mast-cell disease have historically been treated with a regimen of oral, intranasal or topical antihistamines, or oral or intranasal steroids, or, in the case of allergy, allergen injection treatment. Systemic treatment typically requires higher concentrations of the drug compound to be administered to afford an effective concentration to reach the necessary treatment site. Antihistamine compounds are known to have central nervous system activity; drowsiness and drying of mucus membranes are a common side-effect of antihistamine use.
Signaling through immune receptors such as the IgE receptor (FcεRI) involves the recruitment and activation of multiple components of the signaling cascade, including the non-receptor tyrosine kinase, Syk. Syk activation leads to activation of the PLCγ and PI3K pathways and ultimately to mast cell degranulation and activation. Targeting the Syk mRNA would reduce the levels of Syk protein and interrupt the FcεRI pathway. This action would interfere with the IgE mediated mast cell degranulation and release of histamine and other pro-inflammatory mediators.
Inhibition of allergic inflammation in the airways using aerosolized antisense to Syk kinase is reported by Stenton, G. R. et al., (J Immunol. 169:1028-1036 (2002)). Inhibition of Syk expression by means of small interfering RNA (siRNA) in a bronchial epithelial cell line HS-24 and in a rat model of ovalbumin (OA)-induced asthma reportedly inhibited the expression of hallmarks of induced inflammatory response (published international patent application WO 2005007623). Inhibition of expression of genes involved in IgE production using a short hairpin RNA targeting FCεR1A and treatment of IgE-mediated diseases such as asthma and allergic rhinitis were reported in published international patent application WO 2005085443. None of these documents discloses the interfering RNAs of the present invention.
Additional agents and treatment methods would be desirable for targeting the Syk tyrosine kinase, thereby blocking the actions of endogenous mast cell degranulation, and release of histamine and other pro-inflammatory mediators while avoiding the side effects of systemic antihistamine treatment. Embodiments of the present invention address the need in the art for such agents and treatment methods.